Author Affiliations: Department of Obstetrics
and Gynecology, Wayne State University School of Medicine/Hutzel Women’s
Hospital, Detroit, Mich (Drs Hendrix and McNeeley); Division of Public Health
Sciences, Fred Hutchinson Cancer Research Center, Seattle, Wash (Dr Cochrane
and Mr Aragaki); Department of Obstetrics and Gynecology, Carver College of
Medicine (Dr Nygaard) and Department of Epidemiology, College of Public Health
(Dr Wallace), University of Iowa, Iowa City; Department of Obstetrics and
Gynecology, Johns Hopkins University School of Medicine, Baltimore, Md (Dr
Handa); Department of Obstetrics and Gynecology, Medical College of Wisconsin,
Milwaukee (Dr Barnabei); Department of Obstetrics and Gynecology, Washington
Hospital Center, Washington, DC (Dr Iglesia); and Department of Public Health
Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (Dr
Naughton).

ABSTRACT

Context Menopausal hormone therapy has long been credited with many benefits
beyond the indications of relieving hot flashes, night sweats, and vaginal
dryness, and it is often prescribed to treat urinary incontinence (UI).

Objective To assess the effects of menopausal hormone therapy on the incidence
and severity of symptoms of stress, urge, and mixed UI in healthy postmenopausal
women.

Interventions Women were randomized based on hysterectomy status to active treatment
or placebo in either the estrogen plus progestin (E + P) or estrogen alone
trials. The E + P hormones were 0.625 mg/d of conjugated equine estrogen plus
2.5 mg/d of medroxyprogesterone acetate (CEE + MPA); estrogen alone consisted
of 0.625 mg/d of conjugated equine estrogen (CEE). There were 8506 participants
who received CEE + MPA (8102 who received placebo) and 5310 who received CEE
alone (5429 who received placebo).

Main Outcome Measures Incident UI at 1 year among women without UI at baseline and severity
of UI at 1 year among women who had UI at baseline.

Conclusions Conjugated equine estrogen alone and CEE + MPA increased the risk of
UI among continent women and worsened the characteristics of UI among symptomatic
women after 1 year. Conjugated equine estrogen with or without progestin should
not be prescribed for the prevention or relief of UI.

Figures in this Article

Menopausal hormone therapy (MHT) consisting of oral estrogen plus progestin
or estrogen alone has long been used to treat postmenopausal women and, until
recently, was credited with many benefits well beyond the indications for
symptomatic relief of hot flashes, night sweats, and vaginal dryness. One
of the purported benefits of MHT was to improve the symptoms of urinary incontinence
(UI). Biological mechanisms to support this advantage were based on detection
of estrogen receptors in various genitourinary tissues, as well as from observational
studies and anecdotal reports.1- 5

A recent Cochrane review assessing the effects of estrogen use for the
treatment of UI concluded that treatment consisting of estrogen alone is associated
with perceived improvement or cure compared with placebo, but that larger
trials were needed.6 It identified 3 clinical
trials comparing treatments of estrogen plus progestin with placebo, including
the larger Heart and Estrogen/progestin Replacement Study (HERS).7 The review of these studies only suggested that estrogen
plus progestin reduced the likelihood of cure or improvement. With the publication
of the HERS results, the practice of using MHT to treat UI was brought into
question, but the American College of Obstetricians and Gynecologists, in
their response to the results of the Women’s Health Initiative (WHI)
findings stated, “for genitourinary symptoms associated with menopause,
estrogen and progestin have been shown to be beneficial.”8

The WHI estrogen plus progestin (E + P) and estrogen alone double-blind,
placebo-controlled, randomized clinical trials were designed to evaluate the
effects of MHT in preventing coronary heart disease and hip fractures in postmenopausal
women.9 Both trials ended prematurely. The
E + P trial was stopped after an average of 5.6 years of follow-up because
more harm than benefit was observed.10 The
estrogen alone trial was stopped after 7.1 years because an increased risk
of stroke was found with no benefit for coronary heart disease, and sufficient
information was obtained to provide an overall assessment of the risks and
benefits of treatment with estrogen alone.11

The primary aim of this analysis was to determine the effects of MHT
(E + P or estrogen alone) on the 1-year incidence and severity of symptoms
of stress, urge, and mixed UI in healthy postmenopausal women.

METHODS

Study Population

The WHI hormone trials enrolled 27 347 postmenopausal women from
1993 to 1998 at 40 US clinical centers based on hysterectomy status: 16 608
in the E + P trial, who had not had a hysterectomy; 10 739 in the estrogen
alone trial, who had a prior hysterectomy (Figure). The WHI used methods to ensure appropriate age distributions
and adequate power to test the primary hypotheses, to evaluate intermediate
disease outcomes and treatment effects, and to ensure appropriate racial/ethnic
group representation.12 Briefly, women were
recruited primarily by mass mailings and other media announcements and were
eligible if they were aged 50 to 79 years at entry, postmenopausal, and likely
to reside in the study area for 3 years. Women were excluded from the WHI
trials for reasons of competing risk, safety, and adherence or retention.

Figure. Flow Diagram of Women Included in
Analysis of Urinary Incontinence

Reasons for exclusion included breast cancer, other invasive cancer
in the last 10 years, venous thromboembolism, hypertriglyceridemia, having
a medical condition likely to result in death within 3 years, or being unwilling
or unable to be randomized to placebo. Menopausal hormone therapy use at baseline
required a 3-month washout period before enrollment, and women were excluded
if they experienced severe menopausal symptoms at the end of the washout.

All participants were required to complete a 4-week placebo run-in with
an adherence rate of 80% or greater. At baseline, women completed screening
and enrollment questionnaires by interview and self-report, and a physical
examination and blood specimen collection were performed. The study was reviewed
and approved by the human subjects review committees at each participating
institution, and all participants provided written informed consent.

Study Pills

Women randomized in the WHI hormone trials were asked to take a single
daily tablet containing a placebo or active medication (estrogen alone participants:
0.625 mg of conjugated equine estrogen [CEE; Premarin, Wyeth Ayerst, St Davids,
Pa]; E + P participants: 0.625 mg of CEE plus 2.5 mg of medroxyprogesterone
acetate [MPA]). Randomization was performed using a study database distributed
by the WHI Clinical Coordinating Center to the local centers; participants
were randomized to the active treatment or placebo group in each trial at
a 1:1 ratio. The study pill bottles had unique bar codes and computer-based
selection to enable double-blinded dispensing.

The study pills were discontinued without unblinding of clinic staff
or participants if breast cancer, endometrial pathology (hyperplasia not responsive
to treatment, atypia, or cancer), deep-vein thrombosis or pulmonary embolism,
malignant melanoma, meningioma, or a triglycerides level of higher than 1000
mg/dL (11.3 mmol/L) was found. The study pills were also discontinued if any
nonstudy estrogen or progestin was started.

Baseline Assessment and Follow-up

Baseline questionnaires ascertained comprehensive information on participants,
including age, education, occupation, chronic illnesses, time since menopause,
parity, breastfeeding history, duration of hormone use, hysterectomy status,
constipation, current and past smoking, and physical activity (episodes per
week). Participants were asked to categorize their racial or ethnic group
by choosing from the following: American Indian/Alaska Native, Asian/Pacific
Islander, black/African American, Hispanic, Latino, white, or other. Alcohol
consumption and other dietary intake were estimated from a 120-item food frequency
questionnaire.13

Detailed questions on UI were based on similar items used and validated
in previous epidemiological studies14 and included
on a self-administered behavioral and quality of life form (available online
at http://www.nhlbi.nih.gov/resources/deca/whios/index.html). Participants
who answered yes to the question “Have you ever leaked even a very small
amount of urine involuntarily and you couldn’t control it?” were
categorized as having prevalent UI. Those who answered the question “When
do you usually leak urine?” with only “When I cough, laugh, sneeze,
lift, stand up or exercise” were considered to have the symptom of stress
UI and those who answered with only “When I feel the need to urinate
and can’t get to the toilet fast enough” to have urge UI. Those
who marked both responses were considered to have mixed UI. When a participant
responded only “When I am sleeping,” she was classified as having
only UI at night. Women were classified as continent if they responded, “Not
once during the past year” or “no longer leak urine.” Prior
medical or surgical therapy for UI; details on the route of childbirth, vaginal
or Cesarean; or childbirth-related complications were not queried. The baseline
questions on UI were repeated at 1 year in all participants and at 3 years
in a subsample consisting of 8.6% of participants. The subsample was selected
to assess intermediate effects of the interventions (including blood biomarkers),
while keeping costs and clinic burden to a minimum. We characterize incident
UI as the change from baseline to 1 year. We also report the effect at 3 years
in the subsample of the participants.

The WHI participants were asked to bring all current prescription and
nonprescription medications to their first screening interview. Clinic interviewers
entered the names of each medication from the medicine containers into the
WHI database, which assigned drug codes using Medi-Span software.15 Women reported duration of use for each medication.
Information on dose was not captured. Current use of diuretics, anticholinergic
medications, α- and β-blockers, and β agonists were recorded.
Current and prior use of MHT was ascertained by a detailed interview at baseline
that queried women about the type, route of administration, number of pills
per day, age when use was initiated, and duration for each hormonal preparation
ever taken.

Weight was measured to the nearest 0.1 kg on a balance beam scale with
the participant dressed in indoor clothing without shoes. Height was measured
to the nearest 0.1 cm using a wall-mounted stadiometer. Body mass index was
calculated as weight in kilograms divided by height in meters squared. All
women also underwent a standardized baseline pelvic examination. Participants
in the E + P trial had an endometrial aspiration or transvaginal uterine ultrasound
prior to randomization.

Statistical Analysis

Incident or worsening of symptoms focused on stress, urge, and mixed
UI reported at baseline and 1 year. Women stratified by baseline UI were analyzed
in the treatment groups to which they were originally randomized according
to the intent-to-treat principle. Participants with missing data on UI at
baseline or 1 year were excluded from the analyses. Analyses were performed
using SAS statistical software (version 9.0, SAS Institute Inc, Cary, NC).

Logistic regression models were fit with UI status (1 = stress,
urge, or mixed UI at 1 year; 0 = continent at 1 year) to determine
the overall risk of UI among asymptomatic women. Similar logistic regression
models were fit to examine risk of developing a particular type of UI at 1
year as opposed to remaining continent. To examine whether CEE + MPA or CEE
alone had more substantial effects on UI for particular subgroups of women,
we fit a series of logistic regression models. For each model, we included
randomization assignment, a baseline characteristic, and the corresponding
interaction term. Baseline characteristics corresponding to these subgroups
included age; years since menopause; ethnicity; body mass index; prior MHT
use and duration; smoking; history of diabetes, asthma, emphysema, or stroke;
age at first birth; parity; breast feeding; use of diuretics (carbonic anhydrase
inhibitors, loop diuretics, mercurial diuretics, osmotic diuretics, potassium
sparing diuretics, thiazides and thiazide-like diuretics, miscellaneous diuretics,
or combination diuretics), anticholinergics, α- and β-blockers, β
agonists; and alcohol use. Statistical significance of the main effects and
interactions were judged by a nominal α = .05. Results are expressed
as relative risks (RRs).

To determine how MHT affected participants who were incontinent at baseline,
changes in self-reported frequency (daily, weekly, monthly, <monthly, not
at all), amount (none, barely noticeable, soaked underpants, soaked through
to outer clothing), limitations in daily activities (never to very often),
and bother/disturbance (not at all to very disturbing) attributed to UI from
baseline to 1 year were classified as better, same, or worse. Women’s
perceptions of inconvenience and bother, as well as impact on activities of
daily living, have an important influence on treatment decisions. Preliminary
analysis using the response variable indicated little difference between better
and same (for example, the odds of reporting a better frequency of UI from
baseline to 1 year among participants receiving CEE + MPA compared with placebo
was 0.99). For simplicity, the analysis presented herein used the collapsed
response categories of worse compared with same/better. Logistic regression
modeling, similar to the earlier incident analysis, was then performed.

RESULTS

Baseline Characteristics and Prevalence of UI

The study flow for the E + P and estrogen alone trials for women included
in this analysis are shown in the Figure.
Other flow diagrams have been published previously.10,11Table 1 and Table
2 describe baseline demographic and reproductive characteristics,
medical conditions, and health status characteristics of participants who
had baseline and 1-year UI information.

Baseline data on UI was available for 25 597 women (93.6% of all
WHI participants). Among these women, 16 417 or 64.1% (63.4% for E +
P trial; 65.3% for estrogen alone trial) reported UI symptoms within the past
year at baseline. Stress UI was reported by 41.0% of incontinent women in
the E + P trial and 36.7% of those in the estrogen alone trial; urge UI, 34.8%
in the E + P trial and 36.4% in the estrogen alone trial; and mixed UI, 23.8%
in the E + P trial and 26.2% in the estrogen alone trial. Finally, UI only
at night was reported by 0.5% of E + P trial participants and 0.7% of estrogen
alone trial participants. There were no differences in participant characteristics
by baseline hormone use. Participants with mixed UI tended to have leakage
more frequently and tended to report more impact on quality of life in terms
of activity limitations and bother attributed to UI (Table 3).

Women with missing UI data at baseline or 1 year in both MHT trials
were more likely to be younger, to be from a racial/ethnic minority group,
to consume less alcohol, and to be less healthy (ie, more sedentary, poorer
self-reported health, and more likely to have emphysema or Parkinson disease).
For the estrogen alone trial, women with missing UI data were more likely
to report asthma, while E + P trial women with missing UI data were more likely
to report being closer to menopause, obese, and a current smoker and to have
a history of colitis (data available from authors on request).

Participant Follow-Up

At 1 year, vital status was known for 99.9% of participants, including
0.2% who were deceased and 0.1% who were lost to follow-up. During the first
year, 9.7% of women receiving CEE + MPA and 6.6% receiving placebo stopped
taking study pills for various reasons. Overall, the rate of adherence (taking
80% of the pills) to the study protocol was 74% in the CEE + MPA group and
81% in the placebo group at 1 year.

For the estrogen alone trial at 1 year, vital status was known for 100%
of participants, including 0.4% who were deceased. During the first year,
study pills were stopped for various reasons by 8.4% of women randomized to
CEE alone and 8.0% of women randomized to placebo. Overall, 77.4% of women
randomized to CEE alone and 81.4% of women randomized to placebo were adherent
(taking at least 80% of pills) at 1 year.

When comparing amount, degree of bother, and limitations, there were
no differences by treatment group for either estrogen alone or E + P trial
participants, except for degree of bother in those treated with estrogen alone.
In this subgroup analysis, rates of bother were a little, not at all, or somewhat
(29% for CEE alone compared with 8% for placebo), very (41% vs 55%) and extremely
disturbing (30% vs 37%, respectively) (P = .04).

Table 4 includes RRs by subgroups
corresponding to interactions that were significant at P<.05 for stress, mixed, or urge UI. Older women and women who have
been postmenopausal for a longer duration tended to be at higher risk for
MHT effects on incident stress UI (P<.001 for
CEE + MPA and P = .002 for CEE alone with
respect to interaction with age). Similar age trends can be seen for urge
and mixed UI for estrogen alone (P≤.05). Although
the interactions between prior MHT use and CEE + MPA, diabetes and CEE + MPA,
and smoking and CEE alone achieved nominal statistical significance (P<.05) in modifying the risk for stress, urge, and mixed
UI, respectively, these findings are within the realm of chance in that there
does not appear to be any pattern between UI types or MHT treatments or any
biological mechanism explaining these findings. Table 4 displays the main comparisons of interest (a total of 2
trials × 3 types of UI × 18 baseline characteristics
= 108 comparisons made; complete data available on request).

Interaction for stress UI and CEE + MPA is probably a chance finding
for small groupings such as women who used β-blockers. Ethnicity, body
mass index, duration of prior hormone use, asthma, emphysema, stroke, age
at first birth, parity, breastfeeding, use of thiazide or loop diuretics,
anticholinergics, calcium channel blockers, opiates, sedatives, or alcohol
did not substantially alter the effect of MHT on the incidence of stress UI.
No subgroups of women were identified to be at significantly higher or lower
risk of incident urge or mixed UI. Subgroup analyses did not show a significant
effect of race/ethnicity on the effect of MHT on UI (data available on request).

Because of the slight imbalance of baseline characteristics and treatment
assignment in Table 1 and Table 2 (ie, emphysema by CEE + MPA assignment and parity
by estrogen alone assignment), we also adjusted for emphysema in a sensitivity
analysis. The RR for stress UI changed from 1.87 to 1.88, the RR for urge
UI changed from 1.15 to 1.13, and the RR for mixed UI changed from 1.49 to
1.48. Adjustment for parity in the regression models corresponding to the
estrogen alone trial did not change any of the RRs.

To account for different definitions of UI, we performed a sensitivity
analysis and found that the risk of incident UI due to MHT was robust to multiple
definitions of UI (ie, increasing the frequency threshold used to define UI; Table 5). For example, if we change the definition
for UI from “within the last year” to “more than once a
week,” the RR for stress UI changes slightly from 1.87 (95% CI, 1.61-2.18)
to 2.28 (95% CI, 1.91-2.73). Therefore, regardless of whatever definition
of UI is thought to be clinically meaningful, these results still apply.

When we assessed worsening of UI by type of UI (urge, stress, and mixed)
at baseline, overall worsening was independent of type of UI. The exception
to this was the effect of CEE + MPA on worsening of frequency, for which the
RR was 1.41 (95% CI, 1.21-1.64) for stress UI; 1.15 (95% CI, 1.02-1.30) for
urge UI; and 1.58 (95% CI, 1.41-1.77) for mixed UI. In the estrogen alone
trial, the effect on worsening of amount and degree of bother differed by
type of UI at baseline (RR for amount was 2.18 [95% CI, 1.69-2.81] for stress
UI; 1.27 [95% CI, 1.02-1.58] for urge UI; and 1.49 [95% CI, 1.17-1.90] for
mixed UI; RR for degree of bother was 1.65 [95% CI, 1.42-1.93] for stress
UI; and 1.21 [95% CI, 1.04-1.40] for urge UI; 1.78 [95% CI, 1.48-2.14] for
mixed UI), but all types of UI were worsened by CEE alone. Because MHT worsened
symptoms for all 3 types of UI, subgroup analysis of UI worsening was performed
by combining all 3 types of UI, thereby limiting the number of comparisons
to a manageable amount.

A sensitivity analysis showed that the risk of increased amounts of
urine leakage due to MHT use (quantified in our study by how much urine had
soaked through underpants or outer clothing) was robust to amount of protection
used. For example, if we only included participants whose protection (none,
mini-pad, menstrual pad, diaper, or other) at baseline either stayed the same
or increased at 1 year (eg, using mini-pads at baseline and diapers at 1 year),
worsening of amount was relatively unchanged (RR, 1.20; 95% CI, 1.06-1.36)
in our main analysis and among participants whose protection at baseline remained
the same or increased (RR, 1.24; 95% CI, 1.09-1.42) at 1 year.

Subgroup analysis among women receiving CEE alone compared with placebo
showed that incontinent women who were older (P = .004)
and had a lower body mass index (P = .002)
had more leakage. Table 6, Table 7, Table 8, and Table 9 show selected
subgroups, most of which achieved a nominal level of statistical significance
(a total of 2 treatments × 4 types of worsening × 18 baseline
characteristics = 144 comparisons made; complete data available on request).
Similar but more modest trends were seen for CEE + MPA with older and thinner
women experiencing increased amounts of urine leakage.

Among women receiving CEE alone compared with placebo, women who were
older (P<.001) and had a lower body mass index
(P<.001) had an increased frequency of UI. Similar
trends were seen in the E + P trial. Limitations were increased for women
who were younger (P = .01) and further
from menopause (P<.001). Degree of bother increased
for older women closer to menopause who were receiving CEE + MPA or CEE alone.
Race/ethnicity did not modify the effect of MHT on UI (data available on request).

Prior hormone use, duration of use, and treatment assignment had some
nominally significant interactions at P<.01, but
no coherent pattern emerged. Participants with no prior hormone use were more
likely to be bothered by UI at 1 year than at baseline. Smoking, diabetes,
asthma, or diuretic use had no significant interaction with the effect of
CEE + MPA or CEE alone on UI symptoms.

UI at 3 Years

To determine the longer-term effect of MHT on UI, we examined data in
an 8.6% subsample of participants (oversampled for minorities) at 3 years.
For the E + P trial, the subsample of participants at 3 years consisted of
775 participants receiving active treatment and 736 receiving placebo. The
subsample in the estrogen alone trial consisted of 577 participants receiving
active treatment and 612 participants receiving placebo.

Estrogen Plus Progestin

At 1 year, women in the CEE + MPA subsample compared with placebo had
a RR of 1.33 (95% CI, 0.99-1.79) for UI, which was similar to the entire CEE
+ MPA sample (RR, 1.39; 95% CI, 1.27-1.52). Continent women in the CEE + MPA
subsample continued to be at higher risk for UI at 3 years. For the participants
in the CEE + MPA subsample who were continent at baseline and 1 year, 39 (25.5%)
of 153 receiving CEE + MPA reported incident UI at 3 years compared with 26
(14.1%) of 185 women who were receiving placebo (RR, 1.81; 95% CI, 1.16-2.84).
Most women who had incident UI at 1 year still had UI at 3 years (51 [70.8%]
of 72 receiving CEE + MPA and 40 [70.2%] of 57 receiving placebo; P = .94 for difference in remaining incontinent by treatment
group).

Estrogen Alone

Women in the CEE alone subsample had a RR of 1.66 (95% CI, 1.19-2.32)
for UI at 1 year, which was similar to the RR of 1.53 (95% CI, 1.37-1.71)
for the entire CEE alone sample. Participants receiving CEE alone tended to
be at higher risk, albeit not significantly so, than participants receiving
placebo at 3 years, with 27 (28.1%) of 96 who were continent at baseline and
1 year reporting incident UI at 3 years compared with 26 (19.1%) of 136 who
were receiving placebo (RR, 1.47; 95% CI, 0.92-2.36). Most women who had incident
UI at 1 year still had UI at 3 years. Of the participants who reported incident
UI at 1 year, 43 (71.7%) of 60 women who were receiving CEE alone and 26 (68.4%)
of 38 receiving placebo were also incontinent at 3 years (P = .73).

COMMENT

In this randomized clinical trial of MHT in a group of healthy postmenopausal
women, treatment with daily tablets of 0.625 mg of conjugated equine estrogen
(CEE alone) or 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone
acetate (CEE + MPA) increased new onset UI among continent women and worsened
the characteristics of UI among already incontinent women. This effect persisted
through 3 years. Although these findings are based on 1 specific type, route
of administration, and dosage of estrogen (with or without progestin), they
are consistent with findings from an observational study that reported use
of several different formulations of E + P and estrogen alone and suggested
an increased risk of UI associated with MHT.16 To
our knowledge, this is the first randomized trial to demonstrate that estrogen
alone increased UI.

The baseline prevalence of UI in the WHI participants is consistent
with some, but not all, past epidemiological studies. An earlier review of
studies described prevalence rates ranging from 17% to 50% for UI symptoms
within the past 12 months.17 Use of a detailed
assessment tool for measuring UI may have provided a slightly different estimate
of overall UI prevalence or its subtypes in our study sample.18 However,
rates in our study are consistent with more recent studies that also defined
UI broadly as any leakage of urine in the last 12 months. These studies have
identified prevalence rates ranging from 41% to 72% in community-dwelling,
midlife, and older women.19- 25

For several decades, estrogen has been 1 of several treatments for UI
in women. This practice was based on assumptions about biological mechanisms,
associations of various symptoms with menopause, and small uncontrolled trials.
The lower urinary tract shares a common embryologic origin with the genital
tract, the urogenital sinus, and estrogen and progesterone receptors are present
in the vaginal epithelium, the urethra, and bladder trigone.1- 4 Estrogen
loss after menopause causes atrophy throughout the genital tract, which may
lead to itching, burning, dryness, and dyspareunia. Coexistent symptoms, including
urinary frequency, urgency, UI, and recurrent urinary tract infections, were
thought to be related to atrophy of the urinary tract. Because MHT has a beneficial
effect on vaginal mucosa, in particular in improving symptoms of atrophic
vaginitis,26 clinicians suggested that MHT
might also improve UI.

Epidemiological studies have reported higher rates of UI in middle-aged
women, and it was postulated that estrogen deficiency was associated with
both menopause and with UI.5 However, in a
large cross-sectional Study of Osteoporotic Fractures, estrogen use by postmenopausal
women was associated with an almost 2-fold increased risk of daily UI, after
adjusting for various factors.14 These findings,
reported in 1996, had little impact on subsequent treatment recommendations,
and estrogens continued to be viewed as a viable treatment for UI.27- 29

Early uncontrolled case series analyses suggested a benefit of estrogen,
in various forms, on urinary tract symptoms and urodynamic findings. However,
clinical trials of the effect of estrogen therapy on UI have had mixed results.
Most were small and of short duration, and the majority showed no improvement
in the number of incontinent episodes per week.30- 34 In
some of these trials, various combinations of pharmacological agents along
with estrogen were used to treat UI, and benefit could be attributed to combination
therapy, not simply to estrogen alone.35 In
1 of the few randomized trials assessing the impact of combined hormone therapy
on UI as the primary outcome, 83 women received cyclic hormone therapy compared
with placebo.36 After 3 months of cyclic hormone
therapy, there were no differences in clinical or quality-of-life variables
between the treated and untreated groups. In the largest randomized clinical
trial to date prior to WHI, measures of UI and frequency were obtained from
women with heart disease.7 Of 1525 women who
reported at least weekly UI, the use of combined E + P increased the severity
and frequency of urge and stress UI.

A meta-analysis of 28 trials of various hormone preparations with a
total of 2926 women (sample sizes ranging from 16 to 1525 women) assessed
the effect of estrogen treatment on UI.6 In
the 15 trials that compared a total of 374 women randomized to estrogen and
344 to placebo, subjective cure and improvement rates were higher in women
receiving estrogen for both urge UI (35/61 vs 16/58 on placebo) and stress
UI (46/107 vs 29/109). In contrast, based largely on the HERS results, the
authors concluded that estrogen plus progestin therapy was associated with
reduced subjective cure or improvement of UI. Like HERS, we found that estrogen
plus progestin therapy increased the risk of UI. However, our results found
similar increased risk in women taking estrogen alone.

In light of the biological plausibility that MHT would improve UI, it
is important to consider recent advances in basic science research to understand
the mechanisms by which hormone treatment could worsen this condition. Although
basic science in this area is limited, a recent placebo-controlled, randomized
clinical trial of estrogen alone sheds light on this issue. Women receiving
2 mg of oral estradiol valerate over 6 months showed significant decreases
in total periurethral collagen.37 Profound
effects on collagen metabolism were observed and included stimulation of collagen
degradation via increased matrix metalloproteinase-2 activity. Urethral closure
is dependent on the integrated action of the suburethral vaginal wall, the
pubourethral ligaments, the pubococcygeus muscles, and the paraurethral connective
tissues. For all of these structures, connective tissue is a crucial element.
Consequently, damage in the paraurethral connective tissue connecting these
structures to one another and to the urethra will cause ineffective urethral
closure, thus setting the stage for UI. Further research evaluating the effects
of estrogen alone compared with estrogen plus progestin on various biological
mechanisms, such as collagen metabolism, may provide important additional
insights on the mechanisms of action of these preparations on UI.

We studied only 0.625 mg/d of conjugated equine estrogens (estrogen
alone trial) or 0.625 mg/d of conjugated equine estrogens plus 2.5 mg/d of
medroxyprogesterone acetate (E + P trial). Therefore, our ability to generalize
these findings to women taking other MHT formulations is limited. We cannot
address the impact of surgery for UI or changes in treatment over time because
we did not collect those data. Analysis of smaller subgroups for some categories
(eg, women aged 50-54 years), although of interest, may have unstable estimates
and therefore were not performed. Further research on the effects of different
estrogen formulations on pathophysiological changes associated with UI is
needed.

In conclusion, these results from a large, double-blind, placebo-controlled,
randomized clinical trial, conducted in multiple centers with an ethnically
diverse group of healthy postmenopausal women, indicate that MHT use does
not confer protection against any type of UI. On the contrary, both CEE alone
and CEE + MPA increased risk of new onset UI among continent women and worsened
the characteristics of UI among symptomatic women. Considerations regarding
the use of hormone therapy by postmenopausal women for any duration should
incorporate the current findings into the established risks and benefits of
these agents.

Role of the Sponsor: The National Heart, Lung,
and Blood Institute participated in the design, conduct, and oversight of
the trial and reviewed this report. Wyeth-Ayerst provided study pills only
and had no involvement in the design or conduct of the trial.

Acknowledgment: The Women’s Health Initiative
(WHI) Steering Committee gratefully acknowledges the dedicated efforts of
the investigators and staff, who are listed at http://www.whi.org.
The WHI also recognizes the WHI participants for their extraordinary commitment
to the WHI program. We thank Andrea LaCroix, PhD, for her critical evaluation
and review of the manuscript.

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